Project Portfolio – Pandora Endocrine Innovation B.V. (PEI)
The project portfolio of Pandora Endocrine Innovation (PEI) has been focused so far on Women’s Health and Men’s Health and on the endocrine treatment of serious COVID-19, but will shift to the endocrine treatment of cancer, especially advanced breast and prostate cancer and on the treatment of neurological diseases such Anorexia Nervosa, Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS) with a new oral estrogen.*
1. Women’s and Men’s Health
1.1 Oral hormonal male contraception (MANTE) *
Product: Oral male contraceptive containing 120 mg of the gonadotrophin releasing hormone (GnRH) antagonist Relugolix and 250-500 mg DHEA.
Concept: Suppression of spermatogenesis for hormonal contraception in males also inhibits testosterone, interfering with sexual function as well as estrogens causing comparable estrogen deficiency problems as in women. Oral substitution of testosterone is impossible due to first-pass liver breakdown of testosterone. The natural adrenal androgen DHEA is metabolized after oral intake by the liver into testosterone and thereby delivers testosterone substitution. A relatively high dose of DHEA is needed to achieve normal testosterone levels. At such high dose DHEA is also metabolized into estradiol (E2), but is case estrogen replacement is insufficient, estrogen function can be further replaced by adding an estrogen**. So far androgenic progestins have been investigated for oral male contraception, but for the MANTE method the oral GnRH antagonist Relugolix will be used to suppress spermatogenesis, thereby also avoiding the side effects of the androgenic progestins.
The MANTE concept was presented on June 6, 2024 at a meeting of the UN Population Council in New York and published in the journal Contraception in December 2024 as “New endocrine method of oral male contraception” by Herjan JT Coelingh Bennink
Patent: MANTE is patent protected on June 3, 2024.
Status project: Phase 2 dose finding study comparing 250 and 500 mg DHEA
1.2 Oral contraception with RElugolix and an Estrogen** without progestins for Women (REW)
Product: A new continuous regimen without pill pauses and without menstrual bleedings for female oral contraception and the treatment of endometriosis containing 40 mg of the oral GnRH antagonist Relugolix, a low dose of an orally active estrogen and 50-100 mg dehydroepiandrosterone (DHEA).
Concept: In the new REW concept of combined oral contraception, progestins are replaced by the oral GnRH antagonist Relugolix and an oral estrogen and DHEA are added as replacement of the loss of respectively E2 and testosterone due to the ovarian suppression
On May 30, 2023 “Breast Cancer Research (BCR)” published the Perspective Review article “Progesterone from ovulatory menstrual cycles is an important cause of breast cancer” by Herjan J.T. Coelingh Bennink, Iman J. Schultz, Marcus Schmidt, V. Craig Jordan, Paula Briggs, Jan F.M. Egberts, Kristina Gemzell-Danielsson, Ludwig Kiesel, Kirsten Kluivers, Jan Krijgh, Tommaso Simoncini, Frank Z. Stanczyk and Robert D. Langer.
In this narrative review paper a highly significant relationship is demonstrated between the number of menstrual cycles a women experiences during her reproductive life and her risk to develop BCa. The analysis of clinical and molecular data in this article strongly suggest that this cycle related BCa risk is related to progesterone and not to estradiol. Progesterone is an important cause of BC by stimulating proliferation of normal breast epithelium during the luteal phase of the MC through the paracrine factors WNT4 and RANKL. Progesterone also appears to upregulate the expression of the DNA mutator enzyme APOBEC3B during this phase of the MC. These effects of progesterone likely increase the accumulation of mutations in long-lived mammary stem and progenitor cells. Estrogens, testosterone (as precursor of E2) and most environmental factors that are related to the risk of BCa may stimulate the growth of already existing ER+/PR+ BCa, but have only mild proliferative effects on normal breast epithelium and are therefore unlikely to cause BCa.
Patent: A new oral estrogen will be the innovative factor allowing patent protection of REW
Status project: Phase 2 dose finding study comparing three different doses of the estrogen.
1.3 Estrogen replacement therapy with an estrogen** and relugolix without progestins (RERT)
Product: A new continuous regimen without pill pauses and without menstrual bleedings for the perimenopausal transition and postmenopausal estrogen replacement therapy (ERT) containing 40 mg of the oral GnRH antagonist Relugolix and a low dose of an orally active estrogen.
Concept: This RERT concept is based on a combination of an oral GnRH antagonist and an orally active estrogen. As mentioned under 1.2, progesterone from normal menstrual cycles causes most breast cancer (BCa), whereas estrogens and androgens may stimulate existing hormone receptor positive BCa, but do not cause BCa. Synthetic progestins play the same role as progesterone and should therefore be avoided as much as possible in ERT.
Patent: A new oral estrogen will be the innovative factor allowing patent protection of RERT
Status project: Phase 2 dose finding study comparing three different doses of the estrogen.
Infertility
1.4 Improvement of embryo implantation during IVF (VABIO)
Product: A new orally active estrogen** to improve embryo implantation during IVF/ICSI infertility treatment
Concept: This VABIO concept is based on the oral use of a new orally active estrogen to improve the intra-uterine microbioma.
Patent: A new oral estrogen will be the innovative factor allowing patent protection of VABIO
Status project: Phase 2 dose finding study comparing three different doses of the estrogen.
